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The landscape of somatic mutation in normal colorectal epithelial cells

Henry Lee-Six, Peter Ellis, Robert J. Osborne, Mathijs A. Sanders, Luiza Moore, Nikitas Georgakopoulos, Franco Torrente, Ayesha Noorani, Martin Goddard, Philip Robinson, Tim H. H. Coorens, Laura O’Neill, Christopher Alder, Jingwei Wang, Rebecca C. Fitzgerald, Matthias Zilbauer, Nicholas Coleman, Kourosh Saeb-Parsy, Inigo Martincorena, Peter J. Campbell, Michael R. Stratton
doi: https://doi.org/10.1101/416800
Henry Lee-Six
1Wellcome Trust Sanger Institute, Hinxton, UK
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Peter Ellis
1Wellcome Trust Sanger Institute, Hinxton, UK
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Robert J. Osborne
1Wellcome Trust Sanger Institute, Hinxton, UK
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Mathijs A. Sanders
1Wellcome Trust Sanger Institute, Hinxton, UK
2Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Luiza Moore
1Wellcome Trust Sanger Institute, Hinxton, UK
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Nikitas Georgakopoulos
3Department of Surgery and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK
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Franco Torrente
4Department of Paediatric Gastroenterology, Cambridge University Hospital Trust, Addenbrookes, Cambridge, UK
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Ayesha Noorani
5Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK, and Cambridge University Hospitals NHS Trust, Hills Road, Cambridge, UK
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Martin Goddard
6Department of Pathology, Papworth Hospital NHS Trust, UK
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Philip Robinson
1Wellcome Trust Sanger Institute, Hinxton, UK
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Tim H. H. Coorens
1Wellcome Trust Sanger Institute, Hinxton, UK
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Laura O’Neill
1Wellcome Trust Sanger Institute, Hinxton, UK
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Christopher Alder
1Wellcome Trust Sanger Institute, Hinxton, UK
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Jingwei Wang
1Wellcome Trust Sanger Institute, Hinxton, UK
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Rebecca C. Fitzgerald
5Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK, and Cambridge University Hospitals NHS Trust, Hills Road, Cambridge, UK
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Matthias Zilbauer
4Department of Paediatric Gastroenterology, Cambridge University Hospital Trust, Addenbrookes, Cambridge, UK
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Nicholas Coleman
7Department of Pathology, University of Cambridge, Cambridge, UK and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Kourosh Saeb-Parsy
3Department of Surgery and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK
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Inigo Martincorena
1Wellcome Trust Sanger Institute, Hinxton, UK
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Peter J. Campbell
1Wellcome Trust Sanger Institute, Hinxton, UK
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Michael R. Stratton
1Wellcome Trust Sanger Institute, Hinxton, UK
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Abstract

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ∼1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 13, 2018.
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The landscape of somatic mutation in normal colorectal epithelial cells
Henry Lee-Six, Peter Ellis, Robert J. Osborne, Mathijs A. Sanders, Luiza Moore, Nikitas Georgakopoulos, Franco Torrente, Ayesha Noorani, Martin Goddard, Philip Robinson, Tim H. H. Coorens, Laura O’Neill, Christopher Alder, Jingwei Wang, Rebecca C. Fitzgerald, Matthias Zilbauer, Nicholas Coleman, Kourosh Saeb-Parsy, Inigo Martincorena, Peter J. Campbell, Michael R. Stratton
bioRxiv 416800; doi: https://doi.org/10.1101/416800
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The landscape of somatic mutation in normal colorectal epithelial cells
Henry Lee-Six, Peter Ellis, Robert J. Osborne, Mathijs A. Sanders, Luiza Moore, Nikitas Georgakopoulos, Franco Torrente, Ayesha Noorani, Martin Goddard, Philip Robinson, Tim H. H. Coorens, Laura O’Neill, Christopher Alder, Jingwei Wang, Rebecca C. Fitzgerald, Matthias Zilbauer, Nicholas Coleman, Kourosh Saeb-Parsy, Inigo Martincorena, Peter J. Campbell, Michael R. Stratton
bioRxiv 416800; doi: https://doi.org/10.1101/416800

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